TY - JOUR
T1 - Structures of topoisomerase V in complex with DNA reveal unusual DNA-binding mode and novel relaxation mechanism
AU - Osterman, Amy
AU - Mondragón, Alfonso
N1 - Funding Information:
We thank E Smith and V Tokars for comments on the manuscript, H Mangalapalli for help with activity assays and E Campos Chavez and A Grigorescu for help with the DLS experiments as well as other members of the Mondragón laboratory for help and suggestions. Research was supported by the NIH (R35-GM118108 to AM). We acknowledge the help from the Northwestern University Structural Facility and the beamline scientists at LS-CAT/Sector 21 at the Advanced Photon Source, Argonne National Laboratory. LS-CAT/Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor. Support from the RH Lurie Comprehensive Cancer Center of Northwestern University to the Structural Biology Facility and the Keck Biophysics Facility is acknowledged.
Funding Information:
We thank E Smith and V Tokars for comments on the manuscript, H Mangalapalli for help with activity assays and E Campos Chavez and A Grigorescu for help with the DLS experiments as well as other members of the Mondragón laboratory for help and suggestions. Research was supported by the NIH (R35-GM118108 to AM). We acknowledge the help from the Northwestern University Structural Facility and the beamline scientists at LS-CAT/Sector 21 at the Advanced Photon Source, Argonne National Laboratory. LS-CAT/Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor. Support from the RH Lurie Comprehensive Cancer Center of Northwestern University to the Structural Biology Facility and the Keck Biophysics Facility is acknowledged. Funder Grant reference number Author National Institute of General Medical Sciences R35-GM118108 Alfonso Mondragón Funder Grant reference number Author National Cancer Institute P30-CA060553 Alfonso Mondragón The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Publisher Copyright:
© Osterman and Mondragón.
PY - 2022/8
Y1 - 2022/8
N2 - Topoisomerase V is a unique topoisomerase that combines DNA repair and topoisom-erase activities. The enzyme has an unusual arrangement, with a small topoisomerase domain followed by 12 tandem (HhH)2 domains, which include 3 AP lyase repair domains. The uncommon architecture of this enzyme bears no resemblance to any other known topoisomerase. Here, we present structures of topoisomerase V in complex with DNA. The structures show that the (HhH)2 domains wrap around the DNA and in this manner appear to act as a processivity factor. There is a conformational change in the protein to expose the topoisomerase active site. The DNA bends sharply to enter the active site, which melts the DNA and probably facilitates relaxation. The structures show a DNA-binding mode not observed before and provide information on the way this atyp-ical topoisomerase relaxes DNA. In common with type IB enzymes, topoisomerase V relaxes DNA using a controlled rotation mechanism, but the structures show that topoisomerase V accomplishes this in different manner. Overall, the structures firmly establish that type IC topoisomerases form a distinct type of topoisomerases, with no similarities to other types at the sequence, structural, or mechanistic level. They represent a completely different solution to DNA relaxation.
AB - Topoisomerase V is a unique topoisomerase that combines DNA repair and topoisom-erase activities. The enzyme has an unusual arrangement, with a small topoisomerase domain followed by 12 tandem (HhH)2 domains, which include 3 AP lyase repair domains. The uncommon architecture of this enzyme bears no resemblance to any other known topoisomerase. Here, we present structures of topoisomerase V in complex with DNA. The structures show that the (HhH)2 domains wrap around the DNA and in this manner appear to act as a processivity factor. There is a conformational change in the protein to expose the topoisomerase active site. The DNA bends sharply to enter the active site, which melts the DNA and probably facilitates relaxation. The structures show a DNA-binding mode not observed before and provide information on the way this atyp-ical topoisomerase relaxes DNA. In common with type IB enzymes, topoisomerase V relaxes DNA using a controlled rotation mechanism, but the structures show that topoisomerase V accomplishes this in different manner. Overall, the structures firmly establish that type IC topoisomerases form a distinct type of topoisomerases, with no similarities to other types at the sequence, structural, or mechanistic level. They represent a completely different solution to DNA relaxation.
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U2 - 10.7554/eLife.72702
DO - 10.7554/eLife.72702
M3 - Article
C2 - 35969036
AN - SCOPUS:85138377032
VL - 11
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e72702
ER -